Choju Medical Institute

BackgroundIt has become evident that various different neuropathologies including Alzheimer's disease neuropathologic change, limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), and argyrophilic grain disease (AGD) coexist in patients with Lewy body disease (LBD). However, the effect of these comorbidities on brain atrophy remains understudied.ObjectiveThis study aimed to explore the morphological impacts of comorbidities using voxel-based morphometry (VBM).MethodsThirty-four individuals with a neuropathological diagnosis of LBD were included. Antemortem whole-brain 3D-T1-weighted images were preprocessed using Computational Anatomy Toolbox 12. Associations between gray matter (GM) atrophy and specific comorbid neuropathology, as well as interactions among them, were analyzed using VBM.ResultsNeurofibrillary tangle (NFT) pathology exhibited inverse correlations with GM volumes of the right temporal, bilateral frontal lobes, and left posterior cingulate gyrus. Neuritic plaque (NP) pathology-related GM atrophy was localized to the left posterior cingulate gyrus and parts of the parietal lobes. LATE-NC exhibited inverse correlations mainly in the left temporal lobe and left-dominant limbic lobes including the hippocampi. AGD pathology-related GM atrophy was predominant in the left-dominant limbic lobes and left temporal pole. Small vessel disease (SVD) scores were inversely correlated with GM volumes in the left frontal lobe and bilateral cerebellar hemispheres. Interactions between NFT and LATE-NC were limited to limbic and temporal lobes, while interactions between NFT and NP, SVD and NFT or LATE-NC showed more posterior-dominant distributions.ConclusionsVBM analyses revealed distinct atrophy patterns reflective of isolated neuropathologies. Furthermore, the study suggests that interactions between neuropathologies may influence brain atrophy patterns.

Whether the level of the inferior mesenteric artery ligation affects the incidence of anastomotic leakage remains unclear. To assess the impact of the level of inferior mesenteric artery ligation on blood flow to the anastomotic site and the incidence of anastomotic leakage using indocyanine green fluorescence imaging. A post hoc analysis of the EssentiAL trial. This study was conducted at 41 tertiary referral centers in Japan. A total of 839 patients with rectal cancer (<12 cm from the anal verge) were included. The incidence of anastomotic leakage and perfusion status were compared between the high and low ligation groups. The median fluorescence time was similar at 25 seconds in both groups (p = 0.74). Although no statistical difference was noted, the high ligation group was more likely to have greater outliers in fluorescence time compared to the low ligation group. The high ligation group demonstrated higher poor perfusion rates than the low ligation group (2.8% vs 1.5%). In the high ligation group, anastomotic leakage occurred in 1 case of poor perfusion where additional resection was not performed by the surgeon's intraoperative judgment. In addition, the additional resection rate nearly doubled with the use of indocyanine green fluorescence imaging. After propensity score matching (129 patients per group), the overall anastomotic leakage rate was 13.2% in the high ligation group and 10.9% in the low ligation group ( p = 0.57). This study was a post hoc analysis, the sample size was small, and the anastomosis methods varied. The level of inferior mesenteric artery ligation did not affect blood flow at the anastomotic site or the incidence of anastomotic leakage statistically, but assessing bowel perfusion using indocyanine green fluorescence imaging can offer clinical benefits, optimizing patient outcomes. See Video Abstract . The Japan Registry of Clinical Trials (jRCTs-CRB3180007), the Japanese Clinical Trials Registry (UMIN-CTR000030240). ANTECEDENTES:No está claro si el nivel de la ligadura de la arteria mesentérica inferior afecta la incidencia de fuga anastomótica.OBJETIVO:Evaluar el impacto del nivel de ligadura de la arteria mesentérica inferior en el flujo sanguíneo al sitio de la anastomosis y la incidencia de fuga anastomótica mediante imágenes de fluorescencia con verde de indocianina.DISEÑO:Análisis post hoc del ensayo EssentiAL.ESCENARIO:Este estudio se realizó en 41 centros de referencia terciarios en Japón.PACIENTES:839 pacientes con cáncer rectal (<12 cm desde el márgen anal).PRINCIPALES MEDIDAS DE RESULTADOS:Se compararon la incidencia de fuga anastomótica y el estado de perfusión entre los grupos de ligadura alta y baja.RESULTADOS:El tiempo de fluorescencia medio fue similar a 25 segundos en ambos grupos (p = 0.74). Aunque no se observó ninguna diferencia estadística, el grupo de ligadura alta tuvo más probabilidades de tener mayores valores atípicos en el tiempo de fluorescencia en comparación con el grupo de ligadura baja. El grupo de ligadura alta demostró tasas de perfusión deficiente más altas que el grupo de ligadura baja (2.8 % frente a 1.5 %). En el grupo de ligadura alta, se produjo una fuga anastomótica en un caso de perfusión deficiente en el que no se realizó una resección adicional según el criterio intraoperatorio del cirujano. Además, la tasa de resección adicional casi se duplicó con el uso de imágenes de fluorescencia con verde de indocianina. Después de la comparación por puntaje de propensión (129 pacientes por grupo), la tasa general de fuga anastomótica fue del 13.2 % en el grupo de ligadura alta y del 10.9 % en el grupo de ligadura baja ( p = 0.57).LIMITACIONES:Este estudio fue un análisis post hoc, el tamaño de la muestra fue pequeño y los métodos de anastomosis variaron.CONCLUSIONES:El nivel de ligadura de la arteria mesentérica inferior no afectó estadísticamente el flujo sanguíneo en el sitio de la anastomosis ni la incidencia de fuga anastomótica, pero la evaluación de la perfusión intestinal mediante imágenes de fluorescencia con verde de indocianina puede ofrecer beneficios clínicos, optimizando los resultados del paciente. (Traducción-Dr. Jorge Silva Velazco)REGISTRO DEL ENSAYO:Registro japonés de ensayos clínicos (jRCTs-CRB3180007), Registro japonés de ensayos clínicos (UMIN-CTR000030240).

PurposeVoxel-based morphometry (VBM) is widely used to investigate white matter (WM) atrophy in patients with progressive supranuclear palsy (PSP). In contrast to high-resolution 3D T1-weighted imaging such as magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequences, the utility of other 3D sequences has not been sufficiently evaluated. This study aimed to assess the feasibility of using a 3D fast low-angle shot sequence captured as a localizer image (L3DFLASH) for VBM analysis of WM atrophy patterns in patients with PSP.MethodsThis retrospective study included 12 patients with pathologically or clinically confirmed PSP, and 18 age- and sex-matched healthy controls scanned with both L3DFLASH and MPRAGE sequences. Image processing was conducted with the Computational Anatomy Toolbox 12 in statistical parametric mapping 12. In addition to the atrophic WM pattern of PSP on VBM, we assessed the WM volume agreement between the two sequences using simple linear regression and Bland–Altman plots.ResultsDespite the slightly larger clusters on MPRAGE, VBM using both sequences showed similar characteristics of PSP-related WM atrophy, including in the midbrain, pons, thalamus, and precentral gyrus. In contrast, VBM showed gray matter (GM) atrophy of the precuneus and right superior parietal lobule exclusively on L3DFLASH. Unlike the measured values of total intracranial volume, GM, and cerebrospinal fluid on MPRAGE, the value of WM was larger on L3DFLASH. In contrast to the total intracranial volume, brainstem, and frontal and occipital lobes, the correlation with WM volume in other regions was relatively low. However, the Bland–Altman plots demonstrated strong agreement, with over 90% of the values falling within the agreement limits.ConclusionBoth MPRAGE and L3DFLASH are useful for detecting PSP-related WM atrophy using VBM.

We present the results for CAPRI Round 54, the 5th joint CASP‐CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo‐trimers, 13 heterodimers including 3 antibody–antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target. A total of 21 941 models submitted by these groups and by 15 CAPRI scorer groups were evaluated using the CAPRI model quality measures and the DockQ score consolidating these measures. The prediction performance was quantified by a weighted score based on the number of models of acceptable quality or higher submitted by each group among their five best models. Results show substantial progress achieved across a significant fraction of the 60+ participating groups. High‐quality models were produced for about 40% of the targets compared to 8% two years earlier. This remarkable improvement is due to the wide use of the AlphaFold2 and AlphaFold2‐Multimer software and the confidence metrics they provide. Notably, expanded sampling of candidate solutions by manipulating these deep learning inference engines, enriching multiple sequence alignments, or integration of advanced modeling tools, enabled top performing groups to exceed the performance of a standard AlphaFold2‐Multimer version used as a yard stick. This notwithstanding, performance remained poor for complexes with antibodies and nanobodies, where evolutionary relationships between the binding partners are lacking, and for complexes featuring conformational flexibility, clearly indicating that the prediction of protein complexes remains a challenging problem.

Due to clinicoradiological similarities, including amnestic cognitive impairment and limbic atrophy, differentiation of argyrophilic grain disease (AGD) from Alzheimer's disease (AD) is often challenging. Minimally invasive biomarkers, especially magnetic resonance imaging (MRI), are valuable in routine clinical practice. Although it is necessary to explore radiological clues, morphometry analyses using new automated analytical methods, including whole-brain voxel-based morphometry (VBM) and surface-based morphometry (SBM), have not been sufficiently investigated in patients with pathologically confirmed AGD and AD. This study aimed to determine the volumetric differences in VBM and SBM analyses between patients with pathologically confirmed AGD and AD. Eight patients with pathologically confirmed AGD with a lower Braak neurofibrillary tangle stage (<III), 11 patients with pathologically confirmed AD without comorbid AGD, and 10 healthy controls (HC) were investigated. Gray matter volumetric changes in VBM and cortical thickness changes in SBM were compared between the two patient groups (i.e., AGD and AD) and the HC group. In contrast to widespread gray matter volume or cortical thickness loss in the bilateral limbic, temporoparietal, and frontal lobes of the AD group, these were limited, especially in the limbic lobes, in the AGD group, compared with that of the HC group. Although bilateral posterior dominant gray matter volume loss was identified in the AD group compared with the AGD group on VBM, there was no significant cluster between these patient groups on SBM. VBM and SBM analyses both showed a different distribution of atrophic changes between AGD and AD.

Echinocandin antifungal drugs, including micafungin, anidulafungin, and caspofungin, have been recently reported to exhibit antiviral effects against various viruses such as flavivirus, alphavirus, and coronavirus. In this study, we focused on micafungin and its derivatives and analyzed their antiviral activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The micafungin derivatives Mi-2 and Mi-5 showed higher antiviral activity than micafungin, with 50% maximal inhibitory concentration (IC50) of 5.25 and 6.51 µM, respectively (3.8 to 4.7-fold stronger than micafungin) and 50% cytotoxic concentration (CC50) of >64 µM in VeroE6/TMPRSS2 cells. This high anti-SARS-CoV-2 activity was also conserved in human lung epithelial cell-derived Calu-3 cells. Micafungin, Mi-2, and Mi-5 were suggested to inhibit the intracellular virus replication process; additionally, these compounds were active against SARS-CoV-2 variants, including Delta (AY.122, hCoV-19/Japan/TY11-927/2021), Omicron (BA.1.18, hCoV-19/Japan/TY38-873/2021), a variant resistant to remdesivir (R10/E796G C799F), and a variant resistant to casirivimab/imdevimab antibody cocktail (E406W); thus, our results provide basic evidence for the potential use of micafungin derivatives for developing antiviral agents.

Introductionand importance: TEP might be one of options for treating such a sports hernia.Case presentationAn 18-year-old Japanese male presented with right groin pain for approximately two years. The pain was initially felt on the right side only, especially on kicking. We assessed the patient using laparoscopic examination with an intra-abdominal scope and subsequently diagnosed a sports hernia with a bilateral internal inguinal hernia. We then performed total extraperitoneal repair (TEP) for its treatment. The patient had a good postoperative course and was discharged from our hospital in remission after 3 days. Finally, the patient was able to play soccer without groin pain.Clinical discussionChronic groin pain in athletes can be caused by a bulge in the posterior inguinal wall, consistent with an incipient direct inguinal hernia.ConclusionWe show that intraperitoneal examination with TEP might be one of options for treating such a sports hernia. Endoscopic placement of the retropubic mesh must be considered an important option for this type of hernia.

Characterization of amyloid β (Aβ) oligomers, the transition species present prior to the formation of Aβ fibrils and that have cytotoxicity, has become one of the major topics in the investigations of Alzheimer's disease (AD) pathogenesis. However, studying pathophysiological properties of Aβ oligomers is challenging due to the instability of these protein complexes in vitro. Here, we report that conformation-restricted Aβ42 with an intramolecular disulfide bond at positions 17 and 28 (SS-Aβ42) formed stable Aβ oligomers in vitro. Thioflavin T binding assays, nondenaturing gel electrophoresis, and morphological analyses revealed that SS-Aβ42 maintained oligomeric structure, whereas wild-type Aβ42 and the highly aggregative Aβ42 mutant with E22P substitution (E22P-Aβ42) formed Aβ fibrils. In agreement with these observations, SS-Aβ42 was more cytotoxic compared to the wild-type and E22P-Aβ42 in cell cultures. Furthermore, we developed a monoclonal antibody, designated TxCo-1, using the toxic conformation of SS-Aβ42 as immunogen. X-ray crystallography of the TxCo-1/SS-Aβ42 complex, enzyme immunoassay, and immunohistochemical studies confirmed the recognition site and specificity of TxCo-1 to SS-Aβ42. Immunohistochemistry with TxCo-1 antibody identified structures resembling senile plaques and vascular Aβ in brain samples of AD subjects. However, TxCo-1 immunoreactivity did not colocalize extensively with Aβ plaques identified with conventional Aβ antibodies. Together, these findings indicate that Aβ with a turn at positions 22 and 23, which is prone to form Aβ oligomers, could show strong cytotoxicity and accumulated in brains of AD subjects. The SS-Aβ42 and TxCo-1 antibody should facilitate understanding of the pathological role of Aβ with toxic conformation in AD.

The differentiation of Alzheimer's disease (AD) from age-related limbic tauopathies (LT), including argyrophilic grain disease (AGD) and senile dementia of the neurofibrillary tangle type (SD-NFT), is often challenging because specific clinical diagnostic criteria have not yet been established. Despite the utility of specific biomarkers evaluating amyloid and tau to detect the AD-related pathophysiological changes, the expense and associated invasiveness preclude their use as first-line diagnostic tools for all demented patients. Therefore, less invasive and costly biomarkers would be valuable in routine clinical practice for the differentiation of AD and LT. The purpose of this study is to develop a simple reproducible method on magnetic resonance imaging (MRI) that could be adopted in daily clinical practice for the differentiation of AD and other forms of LT. Our newly proposed three quantitative indices and well-known medial temporal atrophy (MTA) score were evaluated using MRI of pathologically-proven advanced-stage 21 AD, 10 AGD, and 2 SD-NFT patients. Contrary to MTA score, hippocampal angle (HPA), inferior horn area (IHA), and ratio between HPA and IHA (i.e., IHPA index) demonstrated higher diagnostic performance and reproducibility, especially to differentiate advanced-stage AD patients with Braak neurofibrillary tangle stage V/VI from LT patients (the area under the receiver-operating-characteristic curve of 0.83, 089, and 0.91; intraclass correlation coefficients of 0.930, 0.998, and 0.995, respectively). Quantitative indices reflecting hippocampal deformation with ventricular enlargement are useful to differentiate advanced-stage AD from LT. This simple and convenient method could be useful in daily clinical practice.